UREAS AND CARBAMATES OF N-HETEROCYCLIC CARBOXYLIC ACIDS AND CARBOXYLIC ACID ISOSTERES

UREES ET CARBAMATES D'ACIDES CARBOXYLIQUES N-HETEROCYCLIQUES ET D'ISOSTERES D'ACIDE CARBOXYLIQUE

English Abstract

This invention relates to novel ureas or carbamates of N-heterocyclic
carboxylic acids and carboxylic acid isosteres, their preparation and use for
treating neurological disorders including physically damaged nerves and
neurodegenerative diseases, and for treating alopecia and promoting hair
growth.

French Abstract

La présente invention concerne de nouvelles urées ou nouveaux carbamates d'acides carboxyliques N-hétérocycliques et d'isostères d'acide carboxylique, leur préparation et leur utilisation pour traiter des troubles neurologiques (y compris des nerfs physiquement altérés) et de maladies neurodégénératives, ainsi que pour traiter l'alopécie et activer la pousse des cheveux.

Claims

What is claimed is:
1. A compound having the formula (I):
<IMG>
where
n is 1-3;
R1 and A are independently selected from the group
consisting of hydrogen, C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, aryl,
heteroaryl, carbocycle, and heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl,
C2-C10 alkenyl or C2-C10 alkynyl;
R2 is a carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, heterocycle, or carboxylic acid isostere is
optionally substituted with one or more substituents
selected from R3, where
R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl,
alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy,
cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl or
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or CO2R4
where R4 is hydrogen or C1-C9 straight or branched chain
alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester, or solvate
thereof;
provided that:
60

A and R1 are not substituted with both hydroxy and oxygen to
form carboxy, or A and R1 are not substituted with both
alkoxy and oxygen to form alkoxycarbonyl, or A and R1 are
not substituted with both amine and oxygen to form amide;
further provided that:
when R2 is COOH, then A and R1 are not both hydrogen, or
phenyl;
further provided that:
when n=1, and D is a bond, and R2 is COOH, and A is
hydrogen,
then R1 is not hydrogen, methyl, ethyl, iso-propyl,
tert-butyl, octyl, chloroethyl, cyclohexyl, substituted or
unsubstituted phenyl,phenylmethyl,phenylethyl,
naphthylenylmethyl, naphthylenylethyl, thiazolyl,
alkoxythiazolyl, substituted or unsubstituted
benzothiazolyl, quinoline, or thioalkyl;
further provided that:
when D is a bond, and R2 is COON, and A is 4-chlorophenyl,
then R1 is not methoxymethyl;
further provided that:
when n=2, and D is a bond, and R2 is COOH, and A is
hydrogen,
then R1 is not hydrogen, substituted or unsubstituted
phenyl, or alkoxythiazolyl;
further provided that:
when n=1, and D is a bond, and R2 is CON (R3)2, and A is
hydrogen,
then R1 is not iso-propyl, tert-butyl, cyclohexyl, cyano
substituted alkyl, or substituted phenyl;
further provided that:
when n=1, and D is a bond,
then R2 is not methoxy;
further provided that:
when n=1 or 2, and D is a bond, and R2 is hydroxy,
then R1 is not substituted phenyl;
61

further provided that:
when n=1 or 2, and D is substituted or unsubstituted
methyl, and R2 is hydroxy or methoxy, and A is hydrogen,
then R1 is not substituted phenyl, hydrogen, methyl, ethyl,
substituted propyl, or hydroxy;
further provided that:
when n=2, and D is hydroxypentyl, and R2 is hydroxy, and A
is hydrogen,
then R1 is not phenyl;
further provided that:
when n=2, and D is ethyl, and R2 is N (R3)2,
then R1 and A cannot be the same;
further provided that:
when n=1, and D is methoxy, and R2 is CON (R3) 2, and A is
methyl,
then R1 is not benzyl;
further provided that:
when n=1, and D is methyl, and R2 is N (R3)2, and A is
hydrogen,
then R1 is not hydroxy;
further provided that:
when D is C1-C2 alkyl, and A is hydrogen,
then R1 is not butyl.
2. The compound of claim 1, wherein R2 is a carbocycle or
heterocycle containing any combination of CH2, O, S, or N in
any chemically stable oxidation state, wherein any of the
atoms of.said ring structure are optionally substituted in
one or more positions with R3.
3. The compound of claim 1, wherein R2 is selected from
the following group:
62

<IMGS>
63

where the atoms of said ring structure may be optionally
substituted at one or more positions with R3.
4. The compound of claim 1, wherein the carboxylic acid
or carboxylic acid isostere of R2 is selected from the group
consisting of:
-COOH, -SO3H, -SO2HNR3,-PO2 (R3)2, -CN, -PO3 (R3) 2,-OR3, -SR3,
-NHCOR3, -N (R3) 2,-CON (R3) 2, -CONH (O) R3, -CONHNHSO2R3,
-COHNSO2R3, and -CONR3CN.
5. The compounds: (2S) -1- (cyclohexyl) carbamoyl-2-
pyrrolidinecarboxylic acid, and compounds 2-151.
6. A pharmaceutical composition, comprising:
a) an effective amount of a urea or carbamate of an
N- heterocyclic carboxylic acid or carboxylic acid
isostere; and
b) a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6, wherein the
urea or carbamate of an N-heterocyclic carboxylic acid or
carboxylic acid isostere comprises a compound of formula
(I):
<IMG>
where
n is 1-3;
R1 and A are independently selected from the group
64

consisting of hydrogen, C1-C9 straight or branched chain
alkyl , C, C2-C9 straight or branched chain alkenyl, aryl,
heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl,
C2-C10 alkenyl or C2-C10 alkynyl;
R2 is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, or heterocycle is optionally substituted with
one or more substituents selected from R3, where
R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl,
alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy,
cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl or
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or CO2R4
where R4 is hydrogen or C1-C9 straight or branched chain
alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester, or solvate
thereof.
8. The pharmaceutical composition of claim 7, wherein R2
is a carbocycle or heterocycle containing any combination
of CH2, O, S, or N in any chemically stable oxidation state,
wherein any of the atoms of said ring structure are
optionally substituted in one or more positions with R3.
9. The pharmaceutical composition of claim 7, wherein R2
is selected from the following group:
65

<IMGS>
66

where the atoms of said ring structure may be optionally
substituted at one or more positions with R3.
10. The pharmaceutical composition of claim 7, wherein R2
is selected from the group consisting of:
-COOH, -SO3H, -SO2HNR3, -PO2 (R3)2, -CN, -PO3 (R3) 2, -OR3, -SR3,
-NHCOR3, -N (R3) 2, -CON (R3) 2, -CONH (O) R3, -CONHNHSO2R3,
-COHNSO2R3, and -CONR3CN .
11. The pharmaceutical composition of claim 7, wherein the
Urea or carbamate of an N-heterocyclic carboxylic acid or
carboxylic acid isostere compound is selected from the
group consisting of compounds 1-151.
12. The pharmaceutical composition of claim 6, further
comprising a neurotrophic factor different from formula
(I) .
13. The pharmaceutical composition of claim 12, wherein
said neurotrophic factor different from formula (I) is
selected from neurotrophic growth factor, brain derived
growth factor, glial derived growth factor, cilial
neurotrophic factor, insulin growth factor and active
truncated derivatives thereof, acidic fibroblast growth
factor, basic fibroblast growth factor, platelet-derived
growth factors, neurotropin-3 and neurotropin 4/5.
14. A method of treating a neurological disorder in an
animal, comprising:
administering to the animal an effective amount of a
urea or carbamate of an N-heterocyclic carboxylic acid or
carboxylic acid isostere to stimulate growth of damaged
peripheral nerves or to promote neuronal regeneration.
15. The method of claim 14, wherein the neurological
67

disorder is selected from the group consisting of
peripheral neuropathies caused by physical injury or
disease state, physical damage to the brain, physical
damage to the spinal cord, stroke associated with brain
damage, and neurological disorders relating to
neurodegeneration.
16. The method of claim 14, wherein the neurological
disorder is selected from the group consisting of
Alzheimer's Disease, Parkinson's Disease, and amyotrophic
lateral sclerosis.
17. The method of claim 14, wherein the neurological
disorder is Alzheimer's disease.
18. The method of claim 14, wherein the neurological
disorder is Parkinson's disease.
19. The method of claim 14, wherein the neurological
disorder is amyotrophic lateral sclerosis.
20. The method of claim 14, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere is non-immunosuppressive.
21. The method of claim 14, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere comprises a compound of formula (I):
<IMG>
68

where
n is 1-3;
R1 and A are independently selected from the group
consisting of hydrogen, C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, aryl,
heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl,
C2-C10 alkenyl or C2-C10 alkynyl;
R2 is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, or heterocycle is optionally substituted with
one or more substituents selected from R3, where
R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl,
alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy,
cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl or
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or CO2R4
where R4 is hydrogen or C1-C9 straight or branched chain
alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester, or solvate
thereof.
22. The method of claim 21, wherein R2 is a carbocycle or
heterocycle containing any combination of CH2, O, S, or N in.
any chemically stable oxidation state, wherein any of the
atoms of said ring structure are optionally substituted in
one ar more positions with R3.
23. The method of claim 21, wherein R2 is selected from the
following group:
69

<IMGS>
70

where the atoms of said ring structure may be optionally
substituted at one or more positions with R3.
24. The method of claim 21, wherein R2 is selected from the
group consisting of:
-COOH, -SO3H, ,-SO2HNR3, -PO2 (R3) 2,-CN, -PO3 {R3) 2, -OR3, -SR3,
-NHCOR3, -N (R3) 2, -CON {R3) 2, -CONH (O) R3, -CONHNHSO2R3,
-COHNSO2R3, and -CONR3CN .
25. The method of claim 14, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere compound is selected from the group consisting of
compounds 1-151.
26. The method of claim 14, further comprising
administering a neurotrophic factor different from formula
{I) .
27. The method of claim 26, wherein said neurotrophic
factor different from formula (I) is selected from the
group consisting of neurotrophic growth factor, brain
derived growth factor, glial derived growth factor, cilial
neurotrophic factor, insulin growth factor and active
truncated derivatives thereof, acidic fibroblast growth
factor, basic fibroblast growth factor, platelet-derived
growth factors, neurotropin-3, and neurotropin 4/5.
28. A method of stimulating growth of damaged peripheral
nerves, comprising:
administering to damaged peripheral nerves an
effective amount of a urea or carbamate of an
N-heterocyclic carboxylic acid or carboxylic acid isostere to
stimulate or promote growth of the damaged peripheral
nerves.
71

29. The method of claim 28, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere is non-immunosuppressive.
30. The method of claim 28, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere comprises a compound of formula (I):
<IMG>
where
n is 1-3;
R1 and A are independently selected from the group
consisting of hydrogen, C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, aryl,
heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl,
C2-C10 alkenyl or C2-C10 alkynyl;
R2 is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, or heterocycle is optionally substituted with
one or more substituents selected from R3, where
R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl,
alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy,
cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl or
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, and
CO2R4 where R4 is hydrogen or C1-C9 straight or branched
72

chain alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester, or solvate
thereof.
31. The method of claim 30, wherein R2 is a carbocycle or
heterocycle containing any combination of CH2, O, S, or N in
any chemically stable oxidation state, wherein any of the
atoms of said ring structure are optionally substituted in
one or more positions with R3.
32. The method of claim 30, wherein R2 is selected from the
following group:
73

<IMGS>
74

where the atoms of said ring structure may be optionally
substituted at one or more positions with R3.
33. The method of claim 30, wherein R2 is selected from the
group consisting of:
-COOH, -SO3H, -SO2HNR3, -PO2 (R3)2, -CN, -PO3 (R3)2, -OR3, -SR3,
-NHCOR3, -N(R3)2, -CON(R3)2, -CONH(O)R3, -CONHNHSO2R3,
-COHNSO2R3, and -CONR3CN.
34. The method of claim 28, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere compound is selected from the group consisting of
compounds 1-151.
35. The method of claim 28, further comprising
administering a neurotrophic factor different from formula
(I).
36. The method of claim 35, wherein said neurotrophic
factor different from formula (I) is selected from the
group consisting of neurotrophic growth factor, brain
derived growth factor, glial derived growth factor, cilial
neurotrophic factor, insulin growth factor and active
truncated derivatives thereof, acidic fibroblast growth
factor, basic fibroblast growth factor, platelet-derived
growth factors, neurotropin-3, and neurotropin 4/5.
37. A method for promoting neuronal regeneration and
growth in animals, comprising:
administering to an animal a therapeutically effective
amount of a neurotrophic Urea or carbamate of an
N-heterocyclic carboxylic acid or carboxylic acid isostere to
promote neuronal regeneration.
38. The method of claim 37, wherein the Urea or carbamate
75

of an N-heterocyclic carboxylic acid or carboxylic acid
isostere is non-immunosuppressive.
39. The method of claim 37, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere comprises a compound of formula (I):
<IMG>
where
n is 1-3;
R1 and A are independently selected from the group
consisting of hydrogen, C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, aryl,
heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl,
C2-C10 alkenyl or C2-C10 alkynyl;
R2 is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, or heterocycle is optionally substituted with
one or more substituents selected from R3, where
R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl,
alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy,
cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl or
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or CO2R4
where R4 is hydrogen or C1-C9 straight or branched chain
alkyl or alkenyl;
76

or a pharmaceutically acceptable salt, ester, or solvate
thereof.
40. The method of claim 39, wherein R2 is a carbocycle or
heterocycle containing any combination of CH2, O, S, or N in
any chemically stable oxidation state, wherein any of the
atoms of said ring structure are optionally substituted in
one or more positions with R3.
41. The method of claim 39, wherein R2 is selected from the
following group:

77

<IMGS>
78

where the atoms of said ring structure may be optionally
substituted at one or more positions with R3.
42. The method of claim 39, wherein R2 is selected from the
group consisting of:
-COOH, -SO3H, -SO2HNR3, -PO2 (R3)2,-CN, -PO3(R3)2,-OR3,-SR3,
-NHCOR3, -N(R3)2, -CON(R3)2, -CONH(O)R3, -CONHNHSO2R3,
-COHNSO2R3, and -CONR3CN.
43. The method of claim 37, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere compound is selected from the group consisting of
compounds 1-151.
44. The method of claim 37, further comprising
administering a neurotrophic factor different from formula
(I).
45. The method of claim 44, wherein said neurotrophic
factor different from formula (I) is selected from the
group consisting of neurotrophic growth factor, brain
derived growth factor, glial derived growth factor, cilial
neurotrophic factor, insulin growth factor and active
truncated derivatives thereof, acidic fibroblast growth
factor, basic fibroblast growth factor, platelet-derived
growth factors, neurotropin-3, and neurotropin 4/5.
46. A method for preventing neurodegeneration in an
animal, comprising:
administering to an animal an effective amount of a
Urea or carbamate of an N-heterocyclic carboxylic acid or
carboxylic acid isostere to prevent neurodegeneration.
47. The method of claim 46, wherein the neurodegeneration
is Alzheimer's disease.
79

48. The method of claim 46, wherein the neurodegeneration
is Parkinson's disease.
49. The method of claim 46, wherein the neurodegeneration
is amyotrophic lateral sclerosis.
50. The method of claim 46, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere is non-isostere.
51.. The method of claim 46, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere comprises a compound of formula (I):
<IMG>
where
n is 1-3;
R1 and A are independently selected from the group
consisting of hydrogen, C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, aryl,
heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl,
C~-C10 alkenyl or C2-C10 alkynyl;
R2 is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, or heterocycle is optionally substituted with
one or more substituents selected from R3, where
R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl,
80

alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy,
cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched
chain alkyl, C~-C6 straight or branched chain alkenyl or
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or CO2R4
where R4 is hydrogen or C1-C9 straight or branched chain
alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester, or solvate
thereof.
52. The method of claim 51, wherein R2 is a carbocycle or
heterocycle containing any combination of CH~, O, S, or N in
any chemically stable oxidation state, wherein any of the
atoms of said ring structure are optionally substituted in
one or more positions with R3.
53. The method of claim 51, wherein R2 is selected from the
following group:
81

<IMGS>
82

where the atoms of said ring structure may be optionally
substituted at one or more positions with R3.
54. The method of claim 51, wherein R2 is selected from the
group consisting of:
-COOH, -SO3H, -SO2HNR3, -PO2, (R3) 2, -CN, -PO3 (R3) 2, -OR3, -SR3,
-NHCOR3, -N (R3) 2, -CON (R3) 2, -CONH (O)R3, -CONHNHSO2R3,
-COHNSO2R3, and -CONR3CN .
55. The method of claim 46, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere compound is selected from the group consisting of
compounds 1-151.
56. The method of claim 46, further comprising
administering a neurotrophic factor different from formula
(I) .
57. The method of claim 56, wherein said neurotrophic
factor different from formula (I) is selected from the
group consisting of neurotrophic growth factor, brain
derived growth factor, glial derived growth factor, cilial
neurotrophic factor, insulin growth factor and active
truncated derivatives thereof, acidic fibroblast growth
factor, basic fibroblast growth factor, platelet-derived
growth factors, neurotropin-3, and neurotropin 4/5.
58. A method for treating alopecia or promoting hair
growth in an animal, which comprises administering to said
animal an effective amount of a urea or carbamate of an
N- heterocyclic carboxylic acid or carboxylic acid isostere.
59. The method of claim 58, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
83

isostere is non-immunosuppressive.
60. The method of claim 58, wherein the Urea or carbamate
of an N-heterocyclic carboxylic acid or carboxylic acid
isostere is a compound of formula (I):
<IMG>
where
n is 1-3;
R1 and A are independently selected from the group
consisting of hydrogen, C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, aryl,
heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl,
C2-C10 alkenyl or C2-C10 alkynyl;
R2, is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, heterocycle, or carboxylic acid isostere is
optionally substituted with one or more substituents
selected from R3, where
R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl,
alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy,
cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl or
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or CO2R4
where R4 is hydrogen or C1-C9 straight or branched chain
alkyl or alkenyl;
84

or a pharmaceutically acceptable salt, ester, or solvate
thereof.
61. The method of claim 60, wherein R2 is a carbocycle or
heterocycle containing any combination of CH2, O, S, or N in
any chemically stable oxidation state, wherein any of the
atoms of said ring structure are optionally substituted in
one or more positions with R3.
62.. The method of claim 60, wherein R2 is selected from the
following group:
85

<IMGS>
86

where the atoms of said ring structure may be optionally
substituted at one or more positions with R3.
63. The method of claim 60, wherein R2 is selected from the
group consisting of
-COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2,-OR3, -SR3,
-NHCOR3, -N (R3) 2,-CON (R3) 2,-CONH (O) R3, -CONHNHSO2R3,
-COHNSO2R3, and -CONR3CN .
64. The method of claim 58, wherein the carboxylic acid or
carboxylic acid isostere is selected from the group
consisting of compounds 1-151.
65. A pharmaceutical composition comprising:
(i) an effective amount of a Urea or carbamate of an
N-heterocyclic carboxylic acid or carboxylic acid
isostere for treating alopecia or promoting hair
growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
66. The pharmaceutical composition of claim 65, wherein
the Urea or carbamate of an N-heterocyclic carboxylic acid
or carboxylic acid isostere is non-immunosuppressive.
67. The composition of claim 65, wherein the carboxylic
acid or carboxylic acid isostere is a compound of formula
(I):
<IMG>
87

where
n is 1-3;
R1 and A are independently selected from the group
consisting of hydrogen, C1-C9 straight or branched chain
alkyl, C2-C9 straight or branched chain alkenyl, aryl,
heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl,
C2-C10 alkenyl or C2-C10 alkynyl;
R2 is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, heterocycle, or carboxylic acid isostere is
optionally substituted with one or more substituents
selected from R3, where
R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl,
alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy,
cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,
thioalkyl, alkylthio, sulfonyl, C1-C6 straight or branched
chain alkyl, C2-C6 straight or branched chain alkenyl or
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or CO2R4
where R4 is hydrogen or C1-C9 straight or branched chain
alkyl or alkenyl;
or a pharmaceutically acceptable salt., ester, or solvate
thereof.
68. The composition of claim 67, wherein R2 is a carbocycle
or heterocycle containing any combination of CH2, O, S, or
N in any chemically stable oxidation state, wherein any of
the atoms,of said ring structure are optionally substituted
in one or more positions with R3.
69. The composition of claim 67, wherein R2 is selected
from the following group:
88

<IMGS>
89

where the atoms of said ring structure may be optionally
substituted at one or more positions with R3.
70. The composition of claim 67, wherein R2 is selected
from the group consisting of:
-COOH, -SO3H, -SO2HNR3, -PO2 (R3) 2, -CN, -PO3 (R3) 2, -OR3, -SR3,
-NHCOR3, -N (R3) 2, -CON (R3) 2, -CONH (O) R3, -CONHNHSO2R3,
-COHNSO2R3, and -CONR3CN.
71. The composition of claim 65, wherein the carboxylic
acid or carboxylic acid isostere is selected from the group
consisting of compounds 1-151.
90

Description

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
- UREAS AND CARBAMATES OF N-HETEROCYCLIC
CARBOXYLIC ACIDS AND CARBOXYLIC ACID ISOSTERES
Related Application Data
This application is a continuation-in-part of U.S.
patent application serial number 60/087,844 to Hamilton
et al., entitled "Ureas and Carbamates of N-Heterocyclic
Carboxylic Acids and Carboxylic Acid Isosteres", filed
June 3, 1998.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel ureas and carbamates
of N -heterocyclic carboxylic acid and carboxylic acid
isosteres, their preparation and use for treating
neurological. disorders including physically damaged
nerves and neurodegenerative diseases, and for treating
alopecia and promoting hair growth.
2. Description of the Prior Art
It has been found that picomolar concentrations of
an immunosuppressant such as FK506 and rapamycin
stimulate neurite out growth in PC12 cells and sensory
nervous, namely dorsal root ganglion cells (DRGs). Lyons
et al., Proc. of Natl. Acad. Sci., 1994 vol. 91, pp.
3191-3195. In whole animal experiments, FK506 has been
shown to'stimulate nerve regeneration following facial
nerve injury and results in functional recovery in
animals with sciatic nerve lesions.
Several. neurotrophic factors effecting specific
neuronal populations in the central nervous system have
been identified. For example, it has been hypothesized
that Alzheimer's disease results from a decrease or loss
1

CA 02333960 2000-12-O1
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_ of nerve growth factor (NGF). It has thus been proposed
to treat Alzheimer's patients with exogenous nerve growth
factor or other neurotrophic proteins such as brain
derived nerve factor (BDNF), filial derived nerve factor,
ciliary neurotrophic factor, and neurotropin-3 to
increase the survival of degenerating neuronal
populations.
Clinical application of these proteins in various
neurological disease states is hampered by difficulties
in the delivery and bioavailability of large proteins to
nervous system targets. By contrast, immunosuppressant
drugs with neurotrophic activity are relatively small and
display excellent bioavailability and specificity.
However, when administered chronically,
immunosuppressants exhibit a number of potentially
serious side effects including nephrotoxicity, such as
impairment of glomerular filtration and irreversible
interstitial fibrosis (Kopp et al., 1991, J. Am. Soc.
Nephrol. 1:162); neurological deficits, such as
involuntary tremors, or non-specific cerebral angina such
as non-localized headaches (De Groen et al., 1987, N.
Engl. J. Med. 317:861); and vascular hypertension with
complications resulting therefrom (Kahan et al., 1989 N.
Engl. J. Med. 321: 1725).
Accordingly, there is a need for small-molecule
compounds which are useful for neurotrophic effects and
for treating neurodegenerative disorders.
Hair loss occurs in a variety of situations. These
situations include male pattern alopecia, alopecia
senilis, alopecia areata, diseases accompanied by basic
skin lesions or tumors, and systematic disorders such as
nutritional disorders and internal secretion disorders.
The mechanisms causing hair loss are very complicated,
but in some instances can be attributed to aging, genetic
disposition, the activation of male hormones, the loss of
L

CA 02333960 2000-12-O1
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_ blood supply to hair follicles, and scalp abnormalities.
The immunosuppressant drugs FK506, rapamycin and
cyclosporin are well known as potent T-cell specific
immunosuppressants, and are effective against graft
rejection after organ transplantation. It has been
reported that topical, but not oral, application of FK506
(Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-
164; Jiang et al., J. Invest. Dermatol. 1995, 104, 523-
525) and cyclosporin (Iwabuchi et al., J. Dermatol. Sci.
1995, 9, 64-69) stimulates hair growth in a dose-
dependent manner. One form of hair loss, alopecia
areata, is known to be associated with autoimmune
activities; hence, topically administered
immunomodulatory compounds are expec~ed to demonstrate
efficacy for treating that type of hair loss. The hair
growth stimulating effects of FK506 have been the subject
of an international patent filing covering FK506 and
structures related thereto for hair growth stimulation
(Honbo et al., EP 0 423 714 A2!. Honbo et al. discloses
the use of relatively large tricyciic compounds, known
for their immunosuppressive effects, as hair revitalizing
agents.
The hair growth and revitalization effects of FK506
and related agents are disclosed in many U.S. patents
(Goulet et al., U.S. Patent No. 5,258,389; Luly et al.,
U.S. Patent No. 5,457,111; Goulet et al., U.S. Patent No.
5,532,248; Goulet et al., U.S. Patent No. 5,189,042; and
Ok et al., L1.S. Patent No. 5,208,241; Rupprecht et al.,
U.S. Patent No. 5,284,840; Organ et al., U.S. Patent No.
5,284,877). These patents claim FK506 related compounds.
Although they do not claim methods ef hair
revitalization, they disclose the known use of FK506 for
affecting hair growth. Similar to FK506 (and the claimed
variations i.n the Honbo et a.l. patent), the compounds
claimed in these patents are relatively large. Further,
3

CA 02333960 2000-12-O1
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_ the cited patents relate to immunomodulatory compounds
for use in autoimmune related diseases, for which FK506's
efficacy is well known.
Other U.S. patents disclose the use of cyclosporin
and related compounds for hair revitalization (Hauer et
al., U.S. Patent No. 5,342,625; Eberle, U.S. Patent No.
5, 284, 826; Hewitt et al. , U. S . Patent No. 4, 996, 193)
.
These patents also relate to compounds useful for
treating aut:oimmune diseases and cite the known use of
cyclosporin and related immunosuppressive compounds for
hair growth.
However, immunosuppressive compounds by definition
suppress the immune system and also exhibit other toxic
side effect_~. Accordingly, there is a need for small
I5 molecule compounds which are useful as hair revitalizing
compounds.
SUMMP~RY OF THE INVENTION
The present invention relates to the surprising
discovery that ureas and carbamates of N-heterocyclic
compounds containing a carboxylic acid or carboxylic acid
isostere moiety may be useful for treating
neurodegenerative disorders and for treating alopecia and
related hair loss disorders. Accordingly, a novel class
of compounds containing an acidic moiety or an isostere
thereof attached to the 2-carbon of an N-heterocyclic
urea or carbamate derivative is provided. These
compounds stimulate neuronal regeneration and outgrowth
and as such are useful for treating neurological
disorders and neurodegenerative diseases. These
compounds also promote hair growth and as such are useful
for treating hair loss disorders. A preferred feature of
the compounds of the present invention is that they do
not exert any significant immunosuppressive activity
and/or are non-immunosuppressive.
4

CA 02333960 2000-12-O1
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A preferred embodiment of this invention is a
compound having the formula (I):
(CHz)n
C-~. , RZ
N D
A~N~O
I
R~
where
n is 1-3;
R, and A are independently selected from the group
consisting of hydrogen, C_-C,3 straight or branched chain
alkyl, Cz-Cq straight or branched chain alkenyl, aryl,
heteroaryl, carbocycle, and heterocycle;
D is a bond, or a C1-Clo straight or branched chain
alkyl, CZ-C,o alkenyl or C,-Clo alkynyl;
RZ is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl,
carbocycle, heterocycle, or carboxylic acid isostere is
optionally substituted with one or more substituents
selected from R3, where
R3 is hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl,
alkaxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy,
cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,
thiaalkyl, alkylthio, sulfonyl, Ci-C~ straight or branched
chain alkyl, CZ-C6 straight or branched chain alkenyl or
alkynyl, aryl, heteroaryl, carbocycle, heterocycle, and
CO~R4 where Rs is hydrogen or C,-C~ straight or branched
chain alkyl or alkenyl;
or or a pharmaceutically acceptable salt, ester, or
solvate thereof;
provided that:
5

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
A and R1 are not substituted with both hydroxy and oxygen
to form carboxy, or A and R1 are not substituted with both
alkoxy and oxygen to form alkoxycarbonyl, or A and R1 are
not substituted with both amine and oxygen to form amide;
further provided that:
when R2 is COOH, then A and R~ are not both hydrogen, or
phenyl;
further provided that:
when n=l, and D is a bond, and RZ is COOH, and A is
hydrogen,
then R1 is not hydrogen, methyl, ethyl, iso-propyl, tert-
butyl, octyl, chloroethyl, cyclohexyl, substituted or
unsubstituteci phenyl, phenylmethyl, phenylethyl,
naphthylenylmethyl, naphthylenylethyl, thiazolyl,
alkoxythiazolyl, substituted or unsubstituted
benzothiazolyl, quinoline, or thioalkyl;
furt=her provided that
when D is a bond, and RZ is COOH, and A is 4-chlorophenyl,
then R1 is not methoxymethyl;
further provided that:
when n=2, and D is a bond, and R~ is COOH, and A is
hydrogen,
then R1 is not hydrogen, substituted or unsubstituted
phenyl, or al.koxythiazolyl;
further provided that:
when n=l, and D is a bond, and R~ is CON (R3) 2, and A is
hydrogen,
then R1 is not iso-propyl, tert-butyl, cyclohexyl, cyano
substituted alkyl, or substituted phenyl;
further provided that:
when n=1, and D is a bond,
then Rz is not methoxy;
further provided that:
when n=1 or 2, and D is a bond, and R~ is hydroxy,
then R1 is not substituted phenyl;
6

CA 02333960 2000-12-O1
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- further provided that:
when n=1 or 2, and D is substituted or unsubstituted
methyl, and RZ is hydroxy or methoxy, and A is hydrogen,
then R1 is not substituted phenyl, hydrogen, methyl,
ethyl, substituted propyl, or hydroxy;
further provided that:
when n=2, and D is hydroxypentyl, and Rz is hydroxy, and A
is hydrogen,
then R1 is not phenyl;
further provided that:
when n=2, and D is ethyl, and R~ is N (R3) ~,
then R, and A cannot be the same;
further provided that:
when n=1, and D is methoxy, and R, is CON (R3)" and A is
methyl,
then R1 is not benzyl;
further provided that:
when n=l, and D is methyl, and R- is N(R3)=, and A is
hydrogen,
then R1 is not hydroxy;
further provided that:
when D is C1-C, alkyl, and A is hydrogen,
then R1 is not butyl.
A preferred embodiment of this invention is (2S)-1-
(cyclohexyl)carbamoyl-2-pyrrolidinecarboxylic acid.
Preferred embodiments of this invention are where Rz
is a carbocycle or heterocycle containing any combination
of CH2, O, S, or N in any chemically stable oxidation
state, where any of the atoms of said ring structure are
optionally substituted in one or more positions with R3.
Especially preferred embodiments of this invention
are where R, is selected from the group below:
7

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
/ N~ N~ / N~ NH OH
N N
HN-N ~--NH N~~ N---N
COOH
SH O OH O
-N N ~NH ~N NH
N=N S~ O ~ HN
0 0
0
~N ~N~ /N
-N NH / 0 I
p~ ~ O-N HN~ SN
\\0 S
OH
/NwO /O N\N NvN
--NH ~~H NH
OH O HS
f S 0
0
OH
NH
OH
0

CA 02333960 2000-12-O1
WO 99/62$79 PCT/US9$/25570
- where the atoms of said ring structure may be optionally
substituted at one or more positions with R3.
Another preferred embodiment of this invention is
where Rz is selected from the group consisting of
-COOH, -S03H, -SOzHNR3, -POZ ( R~' ) z, -CN, -P03 ( R3 ) " -OR3,
-SR3,
-NHCOR3, -N ( R3 ) 2, -CON ( R3 ) 2, -CONH ( 0 ) R3, -CONHNHSOZR3,
-COHNS02R3, and -CONR3CN .
Another preferred embodiment of this invention is a
pharmaceutical composition containing: an effective
amount of a compound of formula (I); and a
pharmaceutically suitable or acceptable carrier. For
neurotrophic compositions a neurotrophic factor different
from formula (I) may also be adminstered or otherwise
included in the composition.
Another preferred embodiment of the invention is a
method of promoting neuronal regeneration and growth in
mammals, comprising administering to a mammal or an
animal an effective amount of a urea or carbamate of an
N-heterocycl:ic carboxylic acid or carboxylic acid
isostere.
Another preferred embodiment ef the invention is a
method of treating a neurological disorder in an animal,
comprising administering to an animal an effective amount
of urea or carbamate of an N-heterocyclic carboxylic acid
or carboxylic acid :isostere to stimulate growth of
damaged peripheral nerves or to promote neuronal
regeneration.
Yet another preferred embodiment of the inventicn is
a method of preventing neurodegeneration in an animal,
comprising administering to an animal an effective amount
of urea or carbamate of an N-heterocyclic carboxylic acid
or carboxylic acid isostere.
Yet another preferred embodiment of the inventicn is
a method of treating alopecia or promoting hair growl:-: in
an animal, comprising administering to an animal an
9

CA 02333960 2000-12-O1
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_ effective amount of urea or carbamate of an N-
heterocyclic carboxylic acid or carboxylic acid isostere.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a photograph of C57 Black 6 mice before
being shaved for the hair regeneration experiment.
Figure 2 is a photograph of mice treated with a
vehicle after six weeks. Figure 2 shows that less than
30 of the shaved area is covered with new hair growth
when the vehicle (control) is administered.
Figure 3 is a bar graph illustrating relative hair
growth on shaved mice treated with N-heterocyclic
carboxylic acids or carboxylic acid isosteres at lumole
per milliliter three times per week. Hair growth was
evaluated after 14 days of treatment.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
"Alkyl" means a branched or unbranched saturated
hydrocarbon chain comprising a designated number of
carbon atoms. For example, C,-C6 straight or branched
alkyl hydrocarbon chain contains 1 to 6 carbon atoms, and
includes but is not limited to substituents such as
methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,
tert-butyl, n-pentyl, n-hexyl, and the like. It is also
contemplated as within the scope of the present invention
that "alkyl" may also refer to a hydrocarbon chain
wherein any of the carbon atoms of said alley' are
optionally replaced with 0, NH, S, or SO2. Fcr example,
carbon 2 of n-pentyl can be replaced with 0 to form
propyloxymethyl.
"Alkenyl" means a branched or unbranched unsaturated
hydrocarbon chain comprising a designated number of
carbon atoms. For example, C~-C6 straight or branched
alkenyl hydrocarbon chain contains 2 to 6 carbon atoms

CA 02333960 2000-12-O1
WO 99/G2879 PCT/US98/25570
- having at least one double bond, and includes but is not
limited to substituents such as ethenyl, propenyl, iso-
propenyl, butenyl, iso-butenyl, tert-butenyl, n-pentenyl,
n-hexenyl, and the like. It is also contemplated as
within the scope of the present invention that "alkenyl"
may also refer to an unsaturated hydrocarbon chain
wherein any of the carbon atoms of said alkenyl are
optionally replaced with O, NH, S, or SO2. For example,
carbon 2 of 4-pentene can be replaced with 0 to form (2-
propene)oxymethyl.
"Alkoxy" means the group -OR wherein R is alkyl as
herein defined. Preferably, R is a branched or unbranc-
hed saturated hydrocarbon chain containing 1 to 6 carbon
atoms.
The term "carbocycle" or refers to an organic cyclic
moiety in which the cyclic skeleton is comprised of only
carbon atoms whereas the term "heterocycle" refers to an
organic cyclic moiety in which the cyclic skeleton
contains one or more heteroatoms selected from nitrogen,
oxygen, or sulfur and which may or may not include carbon
atoms.
Thus, the term "carbocycle" refers to a carbocyclic
moiety containing the indicated number of carbon atoms.
The term "C3-C~ cycloalkyl" , therefore, refers to an
organic cyclic substituent in which three to eight carbon
atoms form a three, four, five, six, seven, or eight-
membered ring, including, for example, a cyclopropyl,
cyclobut~l, cyclopentyl, cyclohexyl, cycloheptyl, or
cyclooctyl ring. As used herein, "carbocycle" may also
refer to two or more cyclic ring systems which are fused
to form, for example bicyclic, tricyclic, or other
similar bridged substituents (e. g. adamantyl).
"Aryl" refers to an aromatic carbocyclic group
having a single ring, for example a phenyl ring; multiple
rings, for example biphenyl; or multiple condensed rings
11

CA 02333960 2000-12-O1
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in which at least one ring is aromatic, for example
naphthyl, 1,2,3,4-tetrahydronaphthyl, anthryl, or
phenanthryl, which can be unsubstituted or substituted
with one or more other substituents as defined above:
The substituents attached to a phenyl ring portion of an
aryl moiety in the compounds of Formula (I) may be
configured in the ortho-, meta-, or para- orientations.
Examples of typical aryl moieties included in the
scope of the present invention may include, but are not
limited to, the following:
\ \ ~ \ /
/ / \
\ / /
/ \ /
/
\ /
/ \ / \
"Aralkyl" refers to alkyl or alkylene (alkenyl)
chain which is substituted with aryl, heteroaryl,
carbocycle or heterocycle, or alternatively one or more
aryl, heteroaryl, carbocycle, or heterocycle(s) which
is/are substituted with alkyl or alkenyl, i.e.
'Alkyl/alkylene which is substituted with Ar' or 'Ar
which is substituted with alkyl/alkylene'.
"Heterocycle" refers to a saturated, unsaturated, or
IL

CA 02333960 2000-12-O1
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aromatic carbocyclic group having a single ring, multiple
rings, or multiple condensed rings, and having at least
one hetero atom such as nitrogen, oxygen, or sulfur
within at least one of the rings. "Heteroaryl" refers to
a heterocycle in which at least one ring is aromatic.
Any of the heterocyclic or heteroaryl groups can be
unsubstituted or optionally substituted with one or more
groups as defined above. Further, bi- or tri-cyclic
het.eroaryl moieties may comprise at least one ring which
is either completely or partially saturated.
As one skilled in the art will appreciate, such
heterocyclic moieties may exist in several isomeric
forms, all of which are encompassed by the present
invention. For example, a 1,3,5-triazine moiety is
isomeric to a 1,2,4-triazine group. Such positional
isomers are to be considered within the scope of the
present invention. Likewise, the heterocyclic or
heteroaryl groups can be bonded to other moieties in the
compounds of the present invention. The points) of
attachment to these other moieties is not to be construed
as limiting on the scope of the invention. Thus, by way
of example, a pyridyl moiety may be bound tc other groups
through the 2-, 3-, or 4-position of the pyridyl group.
All such configurations are to be construed as wit:~:i:~ the
scope of the present invention.
Examples of heterocyclic or heteroaryl moieties
included in the scope of the present invention may
include, but are not limited to, the following:
13

CA 02333960 2000-12-O1
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C~ C> L C
y ~J C~ ~ ~1
~J ~ i,N
i~ iU iC a ii i~N~ ~~_~
O N~ /N N~ N~ N
I N
N / /N
/~N N\ / ~ N / Nw
\ / \ I , N ,,
-N
/ / N\ / N\ / N
i
' \ S \ 0 \
H
/ 0 / I N\ / 0 / N
N
\ ~ t~ \ \
O
/ . / N /
C
0 \ N \ s'
14

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_ "Halo" means at least one fluoro, chloro, bromo, or
iodo moiety.
The term "pharmaceutically acceptable salt, ester,
or solvate" refers to salt, ester, or solvates of the
subject compounds which possess the desired pharmacologi-
cal. activity and which are neither biologically nor
otherwise undesirable. The salt, ester, or solvates can
be formed with inorganic or organic acids such as
acetate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, citrate,
camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, fumarate,
glucoheptanoate, gluconate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, methanesulfonate, naphthylate, 2-
naphthalenesulfonate, nicotinate, oxalate, sulfate,
thiocyanate, tosylate and undecanoate. Base salt, ester,
or solvates include ammonium salts, alkali metal salts
such as lithium, sodium and potassium salts, alkaline
earth metal salts such as calcium and magnesium salts,
salt with organic bases such as dicyclohexylamine salts,
N-methyl-D-glucamine, and salts with amino acids such as
arginine, lysine, and so forth. Also, the basic
nitrogen-containing groups can be quarternized with such
agents as: 1) lower alkyl halides, such as methyl, ethyl,
propyl, and butyl chloride, bromides and iodides; 2)
dialkyl sulfates like dimethyl, diethyl, dibutyl and
diamyl sulfates; 2) long chain alkyls such as decyl,
lauryl, myristyl and stearyl substituted with one or more
halide such as chloride, bromide and iodide; and 9) aryl
or arylalkyl halides like benzyl. and phenethyl bromide
and others.
The compounds of this invention may possess at least
3S one asymmetric center and thus can be produced as

CA 02333960 2000-12-O1
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- mixtures of stereoisomers or as individual enantiomers or
diastereomers. The individual stereoisomers may be
obt=ained by using an optically active starting material,
by resolving a racemic or non-racemic mixture of an
intermediate at some appropriate stage of the synthesis,
or by resolution of the compound of formula (I). It is
understood that the individual stereoisomers as well as
mixtures (racemic and non-racemic) of stereoisomers are
encompassed by the scope of the present invention. The
S-stereoisomer at atom 1 of formula :C is a most preferred
embodiment of the invention.
"Stereoisomers" are isomers that differ only in the
wau the atoms are arranged in space.
"Isomers" are different compounds that have the same
molecular formula and includes cyclic, isomers such as
(iso)indole and other isomeric forms of cyclic moieties.
"Enanti.omers" are a pair of stereoisomers that are
non-superimposable mirror images of each other.
"Diastereoisomers" are stereoisomers which are not
mirror images of each other.
"Racemic mixture" means a mixture containing equal
parts of individual enantiomers. "Non-racemic mixture"
is a mixture containing unequal parts of individual
enantiomers or stereoisomers.
~~Isosteres" are different compounds that have
different molecular formulae but exhibit the same or
similar properties. For example, tetrazole is an
isostere,of carboxylic acid because it mimics the
properties of carboxylic acid even though they both have
very different molecular formulae. Tetrazole is one of
many possible isosteric rep_Lacements for carboxylic acid.
Other carboxylic acid isosteres contemplated by the
present invention include -COOH, -SO~H, -SO~HNR3, -PO~(R3)"
-CN, -P03 (R3) 2, -OR', -SR3, -NHCOR', -N (R3) z, -CON (R3) z,
-CONH (O) R3, -CONHNHSOzR3, -COHNSO~R3, and -CONR3CN.
16

CA 02333960 2000-12-O1
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_ Tn addition, carboxylic acid isosteres can include 5-7
membered carbocycles or heterocycles containing any
combination of CH2, 0, S, or N in any chemically stable
oxidation state, where any of the atoms of said ring
structure are optionally substituted in one or more
positions. The following structures are non-limiting
examples of preferred carbocyclic and heterocyclic
isosteres contemplated by this invention.
/NwN NON /NON NH OH
HN-N/ NH N~I
N- N
COOH
SH O OH p
i\
-N N 'NH ~ N NH
/
N=N S ~ C> HN
0 0
O
/N /Nw /N
NH ~ 0
O-~ 0-N HN-~ S-N
O S
OH
/Nw0 ~O N~ N~
% /
O~NH ~HS~--NH ~NH
~O ~/H
f S 0
0
OH
~NH
o OH
0
m

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
where the atoms of said ring structure may be optionally
substituted at one or more positions with R3. The present
invention contemplates that when chemical substituents
are added to a carboxylic isostere then the inventive
compound retains the properties of a carboxylic isostere.
The present invention contemplates that when a carboxylic
isostere is optionally substituted with one or more
moieties selected from R3, then the substitution cannot
eliminate the carboxylic acid isoster:ic properties of the
inventive compound. The present invention contemplates
that the placement of one or more R' substituents upon a
carbocyclic or heterocyclic carboxylic acid isostere
shall not be permitted at one or more atoms) which
maintains) or is/are integral to the carboxylic acid
isosteric properties of the inventive compound, if such
substituent(s) would destroy the carboxylic acid
isosteric properties of the inventive compound.
Other carboxylic acid isosteres not specifically
exemplified or described in this specification are also
contemplated by the present invention.
The term "preventing neurodegeneration" as used
herein includes the ability to inhibit or prevent
neurodegeneration in patients newly diagnosed as having a
neurodegenerative disease, or at risk of developing a new
degenerative disease and for inhibiting or preventing
further neurodegeneration in patients who are already
suffering from or have symptoms of a neurodegenerative
disease when the compounds are given concurrently.
The term "treatment" as used herein covers any
treatment of a disease and/or condition in an animal,
particularly a human, and includes:
(i) preventing a disease and/or condition from
occurring in a subject which may be predisposed to the
disease and/or condition but has not yet been diagnosed
as having it;
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CA 02333960 2000-12-O1
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(ii) inhibiting the disease and/or condition, i.e.,
arresting its development; or
(iii) relieving the disease and/or condition, i.e.,
causing regression of the disease and/or condition.
The system used in naming the compounds of the
present invention is shown below, using a compound of
formula I as an example.
A compound of the present invention, especially
formula I, wherein n is l, X is O, D is a bond, Rl is
1,l,dimethylpropyl, and R2 is -CN, is named (2S)-1-(1,2-
dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarbonitrile.
"Alopecia" refers to deficient hair growth and
partial or complete loss of hair, including without
limitation androgenic alopecia (male pattern baldness),
toxic alopecia, alopecia senilis, alopecia areata,
alopecia pelada and trichotillomania. Alopecia results
when the pilar cycle is disturbed. The most frequent
phenomenon i:~ a shortening of the hair growth or anagen
phase due to cessation of cell proliferation. This
results in an early onset of the catagen phase, and
consequently a large number of hairs in the telogen phase
during which the follicles are detached from the dermal
papillae, and the hairs fall out. Alopecia has a number
of etiologies, including genetic factors, aging, local
and systemic diseases, febrile conditions, mental
stresses, hormonal problems, and secondary effects of
drugs.
"Pil~r cycle" refers to the life cycle of hair
follicles, and includes three phases:
(1) the anagen phase, the period of active hair
growth which, insofar as scalp hair is
concerned, lasts about three to five years;
(2) the catagen phase, the period when growth stops
and the follicle atrophies which, insofar as
scalp hair is concerned, lasts about one to two
19

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
weeks; and
(3) the telogen phase, the rest period when hair
progressively separates and finally falls out
which, insofar as scalp hair is concerned,
lasts about three to four months.
Normally 80 to 90 percent of the follicles are in the
anagen phase, less than 1 percent being in the catagen
phase, and the rest being in the telogen phase. In the
telogen phase, hair is uniform in diameter with a
slightly bulbous, non-pigmented root. By contrast, in
the anagen phase, hair has a large colored bulb at its
root.
"Promoting hair growth" refers to maintaining,
inducing, stimulating, accelerating, or revitalizing the
germination of hair.
"Treating alopecia" refers to:
(i) preventing alopecia in an animal which may be
predisposed to alopecia; and/or
(ii) inhibiting, retarding or reducing alopecia;
and/or
(iii) promoting hair growth; and/or
(iv) prolonging the anagen phase of the hair cycle;
and/or
(v) converting vellus hair to growth as terminal
hair. Terminal hair is coarse, pigmented, long hair in
which the bulb of the hair follicle is seated deep in the
dermis. Ven us hair, on the other hand, is fine, thin,
non-pigmented short hair in which the hair bulb is
located superficially in the dermis. As alopecia
progresses, the hairs change from the terminal to the
vellus type.
The term ~~neurotrophic" as used herein includes
without limitation the ability to stimulate neuronal
regeneration or growth and/or the ability to prevent or
treat neurodegeneration.

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
The term "non-immunosuppressive" refers to the
inability of the compounds of the present invention to
trigger an immune response when compared to a control
such as FK506 ro cyclosporin A. Assays for determining
immunosuppression are well known to those of ordinary
skill in the art. Specific non-limiting examples of well
known assays include PMA and OKT3 assays wherein mitogens
are used to stimulate proliferation of human peripheral
blood lymphocytes (PBC). Compounds added to such assay
systems are evaluated for their ability to inhibit such
proliferation.
Compounds of the Invention
The present invention relates to the surprising
discovery that carboxylic acid or carboxylic acid
isostere compounds are neurotrophic and are able to treat
alopecia. Accordingly, a novel class of compounds are
provided. A preferred feature of the compounds of the
present invention is that they do not exert any
significant immunosuppressive activity.
Preferred compounds of the present invention contain
carboxylic acid moieties and other isosteric replacements
for carboxylic acid moieties, of which several examples
21

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
are specified herein. Other isosteric replacements for
carboxylic acid moieties, known to those skilled in the
art of medicinal chemistry, are within the scope of the
invention if not otherwise specified.
The neurotrophic compounds of this invention can be
periodically administered to a patient undergoing
treatment for neurological disorders or for other reasons
in which it is desirable to stimulate neuronal
regeneration and growth, such as in various peripheral
neuropathic and neurological disorders relating to
neurodegeneration. The compounds of this invention can
also be administered to mammals other than humans for
treatment of various mammalian neurological disorders.
The novel compounds of the present invention possess
an excellent degree of neurotrophic activity. This
activity is useful in the stimulation of damaged neurons,
the promotion of neuronal regeneration, the prevention of
neurodegeneration, and in the treatment of several
neurological disorders known to be associated with
neuronal degeneration and peripheral neuropathies. The
neurological disorders that may be treated include but
are not limited to: trigeminal neuralgia,
glossopharyngeal neuralgia, Bell's Palsy, myasthenia
gravis, muscular dystrophy, amyotrophic lateral
sclerosis, progressive muscular atrophy, progressive
bulbar inherited muscular atrophy, herniated, ruptured or
prolapsed invertebrate disk syndromes, cervical
spondylosis, plexus disorders, thoracic outlet
destruction syndromes, peripheral neuropathic such as
those caused by lead, dapsone, ticks, prophyria, or
Gullain-Barre syndrome, Alzheimer's disease, and
Parkinson's disease.
The above discussion relating to the utility and
administration of the compounds of the present invention
also applies to the pharmaceutical compositions of the
22

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
_ present invention.
The term "pharmaceutically acceptable carrier" as
used herein refers to any carrier, diluent, excipient,
suspending agent, lubricating agent, adjuvant, vehicle,
delivery system, emulsifier, disintegrant, absorbent,
preservative, surfactant, colorant, flavorant, or
sweetener.
For these purposes the compounds of the present
invention may be administered orally, parenterally, by
inhalation spray, topically, rectally, nasally, buccally,
vaginally or via an implanted reservoir in dosage
formulations containing conventional non-toxic
pharmaceutically-acceptable carriers, adjuvants and
vehicles. The term parenteral as used herein includes
subcutaneous, intravenous, intramuscular,
intraperitoneally, intrathecally, intraventricularly,
intrasternal and intracranial injection or infusion
techniques.
For oral. administration, the compounds of the
present inver_tion may be provided in any suitable dosage
form known in the art. For example, the compositions may
be incorporated into tablets, powders, granules, beads,
chewable lozenges, capsules, liquids, aqueous suspensions
or solutions, or similar dosage forms, using conventional
equipment and techniques known in the art. Tablet dosage
forms are preferred. Tablets may contain carriers such
as lactose and corn starch, and/or lubricating agents
such. as magnesium stearate. Capsules may contain
diluents including lactose and dried corn starch.
Aqueous suspensions may contain emulsifying and
suspending agents combined with the active ingredient.
When preparing dosage form incorporating the
compositions of the invention, the compounds may also be
blended with conventional excipients such as binders,
including gelatin, pregelatinized starch, and the like;
23

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
_ lubricants, such as hydrogenated vegetable oil, stearic
acid, and the like; diluents, such as lactose, mannose,
and sucrose; disintegrants, such as
carboxymethylcellulose and sodium starch glycolate;
suspending agents, such as povidone, polyvinyl alcohol,
and the like; absorbants, such as silicon dioxide;
preservatives, such as methylparaben, propylparaben, and
sodium benzoate; surfactants, such as sodium lauryl
sulfate, polysorbate 80, and the like; colorants such as
F.D.& C. dyes and lakes; flavorants; and sweeteners.
Compositions and methods of the invention also may
utilize controlled release technology. Thus, for
example, the inventive compounds may be incorporated into
a hydrophobic polymer matrix for controlled re~~ease over
a period of days. Such controlled release films are well
known to the art. Particularly preferred are ~ransdermal
delivery systems. Other examples of polymers commonly
employed for this purpose that may be used in the present
invention include nondegradable ethylene-vinyl acetate
copolymer and degradable lactic acid-glycolic acid
copolymers which may be used externally or internally.
Certain hydrogels such as po.ly(hydroxyethylmet~~:acrylate)
or poly(vinylalcohol) also may be useful, but nor shorter
release cycles then the other polymer releases systems,
such as those mentioned above.
To be effective therapeutically as central nervous
systE=m targets, the compounds of the present invention
shou:Ld readily penetrate the blood-brain barrier when
peripherally administered. Compounds which cannot
penetrate the blood-brain barrier can be effectively
administered by an intraventricular route or other
appropriate delivery system suitable for administration
to the brain.
The compounds of the present invention may be
administered in the form of sterile injectable
24

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
preparations, for example, as sterile injectable aqueous
or oleaginous suspensions. These suspensions may be
formulated according to techniques known in the art using
suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparations may also be
sterile injec:table solutions or suspensions in non-toxic
parenterally-acceptable diluents or solvents, for
example, as solutions in 1,3-butanediol. Among the
acceptable vehicles and solvents that may be employed are
water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile, fixed oils are
conventionally employed as solvents or suspending
mediums. For' this purpose, any bland fixed oil may be
employed including synthetic mono- or di-glycerides.
Fatty acids such as oleic acid and its glyceride
derivatives, including olive oil and castor oil,
especially in their polyoxyethylated versions, are useful
in the preparation of injectables. These oil solutions
or suspensions may also contain long-chain alcohol
diluents or dispersants.
The compounds of this invention may also be
administered rectally in the form of suppositories.
These compositions can be prepared by mixing the drug
with. a suitable non-irritating excipient which is solid
at room temperature, but liquid at rectal temperature
and, therefore, will melt in the rectum to release the
drug. Such materials include cocoa butter, beeswax and
polyethylene glycols.
The compounds of this invention may also be
administered topically, especially when the conditions
addressed for treatment involve areas or organs readily
accessible by topical application, including
neurological disorders of the eye, the skin, or the lower
intestinal tract. Suitable topical formulations are
readily prepared for each of these areas.

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/2557fl
For topical application to the eye, or ophthalmic
use, the compounds can be formulated as micronized
suspensions in isotonic, pH adjusted sterile saline, or,
preferably, as solutions in isotonic, pH adjusted sterile
saline, either with or without a preservative such as
benzylalkonium chloride. Alternatively for the
ophthalmic uses the compounds may be formulated in an
ointment such as petrolatum.
For topical application to the skin, the compounds
can be formulated in a suitable ointment containing the
compound suspended or dissolved in, for example, a
mixture with one or more of the following: mineral oil,
liquid petrolatum, white petrolatum, propylene glycol,
polyoxyethylene polyoxypropylene compound, emulsifying
wax and water. Alternatively, the compounds can be
formulated in a suitable lotion or cream containing the
active compound suspended or dissolved in, for example, a
mixture of one or more of the following: mineral oil,
sorbitan monostearate, polysorbate 60, cetyl esters wax,
cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
Topical application for the lower intestinal tract
an be effected in a rectal suppository formulation (see
above) or in a suitable enema formulation.
Dosage levels on the order of about 0.1 mg to about
10,000 mg of the active ingredient compound are useful in
the treatment of the above conditions, with preferred
levels of,about 0.1 mg to about 1,000 mg. The amount of
active ingredient that may be combined with the carrier
materials to produce a single dosage form will vary
depending upon the host treated and the particular mode
of administration. Typically, in vitro dosage-effect
results provide useful guidance on the proper doses for
patient administration. Studies in animal models are
also helpful. The considerations for determining the
26

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
proper dose levels are well known in the art.
It is understood, however, that a specific dose
level for any particular patient will depend upon a
variety of factors including the activity of the specific
compound employed, the age, body weight, general health,
sex, diet, time of administration, rate of excretion,
drug combination, and the severity of the particular
disease being treated and form of administration.
To effectively treat alopecia or promote hair
growth, the compounds used in the inventive methods and
pharmaceutical compositions must readily affect the
targeted areas. For these purposes, the compounds are
preferably administered tapically to the skin.
For topical application to the skin, the compounds
can be formulated into suitable ointments containing the
compounds suspended or dissolved in, for example,
mixtures with one or more of the following: mineral oil,
liquid petrolatum, white petrolatum, propylene glycol,
polyoxyethylene polyoxypropylene compound, emulsifying
wax and water. Alternatively, the compounds can be
formulated into suitable lotions or creams containing the
active compound suspended or dissolved in, for example, a
mixture of one or more of the following: mineral oil,
sorbitan monostearate, polysorbate 60, cetyl ester wax,
cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
The compounds can be administered with other hair
revwtalizing agents. Specific dose levels for the other
hair_ revitalizing agents will depend upon the factors
previously stated and the effectiveness of the drug
combination. Other routes of administration known in the
pharmaceutical art are also contemplated by this
invention.
Specific embodiments of the inventive compounds are
presented in Table I. The present invention contemplates
27

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
employing the compounds of Table I, below, for use in
compositions and methods to prevent and/or treat a
neurological disorder in an animal, and for use in
compositions and methods to treat alopecia and promote
hair growth in an animal, and all other uses suggested in
this specification.
TABLE I
~CH2)n
R
N D
A~N~O
I
R1
No. n D R2 A R1
1 1 bond COOH H cyclohexyl
2 1 bond COOH H a-MethylBenzyl
3 1 bond COOH H 4-MethylBenzyl
4 1 bond Tetrazole H Benzyl
5 1 bond S03H H a-MethylBenzyl
6 1 CHI COOH H 4-MethylBenzyl
7 1 bond SO,HNMe H Benzyl
8 1 bond CN H a-MethylBenzyl
9 1 bond P03H2 H 4-MethylBenzyl
10 2 bond COOH H Benzyl
11 2 bond COOH H a-MethylBenzyl
12 2 bond COON H 2-butyl
13 2 bond COOH H 2-butyl
14 2 bond COOH H Cyclohexyl
15 2 bond PO~HEt H i-propyl
16 2 bond P03HPropyl H ethyl
17 2 bond P03(Et)2 H Methyl
18 2 bond OMe H tert-butyl
28

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
No. n D R2 A R1
19 2 bond OEt H n-pentyl
20 2 bond OPropyl H n-hexyl
21 1 bond OButyl H Cyclohexyl
22 1 bond OPentyl H cyclopentyl
23 1 bond OHexyl H heptyl
24 1 bond SMe H n-octyl
25 1 bond SEt H n-hexyl
26 2 bond SPropyl H n-hexyl
27 2 bond SButyl H n-hexyl
28 2 bond NHCOMe H n-hexyl
29 2 bond NHCOEt H 2-thienyl
30 1 CHI, N(Me)z H adamantyl
31 1 (Ci-I~) N (Me) Et H adamantyl
,
32 1 (CH,).; CON(Me)Z H adamantyl
33 1 (CH~)~ CONHMe H adamantyl
34 1 (CHz)5 CONHEt H adamantyl
35 1 (Cf-I2) CONHPropyl H adamantyl
6
36 1 bond CONH(0)Me H Benzyl
37 1 bond CONH(O)Et H a-methylphenyl
38 1 bond CONH(0)Pro pyl H 4-Methylphenyl
39 2 bond COON H Benzyl
40 2 bond COOH H a-Methylphenyl
41 2 bond COON H 4-Methylphenyl
42 1 CH, COOH Me cyclohexyl
43 1 (CHZ), COOH Et cyclohexyl
44 1 (CI-i2) COOH Prop cyclohexyl
3
45 1 (CHZ)a COOH But cyclohexyl
46 1 (Cf-fz) COOH H cyclohexyl
;
47 1 (CI-i?) COOH H cyclohexyl
b
48 1 (Cf-iz), COOH H cyclohexyl
49 1 (CHz) ~ COOH H cycloi-iexyl
50 1 (CH~); COOH H cyclohexyl
51 1 (CHZ) to COOH H cyclohexyl
52 1 C,H, COOH H cyclohexyl
29

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
No. n D R2 A RI
53 1 2-OH, Et COOH H cyclohexyl
59 1 2butylene COON H cyclohexyl
55 1 i-Pro COOH H cyclohexyl
56 1 tert-Bu COOH H cyclohexyl
57 1 2-vitro COOH H cyclohexyl
Hexyl
58 3 (CHZ)Z CN H cyclohexyl
59 1 (CHZ) ~ CN H cyclohexyl
60 3 bond CONHNHSOZMe H Benzyl
61 3 bond CONHNHSO2Et H a-Methylphenyl
62 3 bond CONHSO.,Me H 4-Methylphenyl
63 2 bond CONHNHSO~Et H Phenyl
64 2 bond CON(Me)CN H a-Methylphenyl
65 2 bond CON(Et)CN H 4-Methylphenyl
66 1 (CHz) z COOH H methyl
67 1 ( CHz ) COOH H ethyl
3
68 1 (CHz)4 COOH H n-propyl
69 1 (CHZ)5 COOH H t-butyl
70 1 (CH,)6 COOH H Pentyl
71 1 ( CHZ ) COOH H Hexyl
,
72 1 (CHz) a COOH H Heptyl
73 1 (CHI) G COOH H Octyl
7 4 1 ( CHZ ) COOH H Nonyl
, ~
75 1 CzH2 COON H Cyclohexyl
N
76 1 bond ~ H cyclohexyl
~
~ ,
HN-N
N
77 1 bond ~ ~ H adamantyl
HN- N

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
- No. n D R2 A R1
N
78 1 bond ~~ H 1,1-dimethylpropyl
HN-N
N
79 1 bond ~~ H trimethoxyphenyl
HN-N
N~
~N
80 1 bond ~ / H cyclohexyl
NH
COOH
N~
~N
81 1 bond ~ / H adamantyl
NH
COOH
N~
~N
82 1 bond ~ / H l,l-dimethylpropyl
NH
COON
N~
~N
83 1 bond / H trimethoxyphenyl
NH
COOH
NH OH
84 1 bond -~~ H cyclohexyl
N- N
NH OH
85 1 bond -~~ H adamantyl
N-N
31

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
_ No. n D R2 A Rl
NH OH
86 1 bond -~~ H 1,1-dimethylpropyl
N- N
NH OH
87 1 bond -~~ H trimethoxyphenyl
N- N
/N~
N
88 1 bond H cyclohexyl
N -
Me Me
/N\
N
S 89 1 bond H adamantyl
N --
Me Me
/N~
N
90 1 bond ~~ H l,l-dimethylpropyl
N --
Me Me
/N~
N
91 1 bond H trimethoxyphenyl
N
Me Me
SH
92 1 bond /~ H cyclohexyl
\ /
N=N
32

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
No. n D R2 A Rl
SH
93 1 bond ~ "~" H adamantyl
\ /
N= N
SH
94 1 bond ~\ H 1,1-dimethylpropyl
\ /
N=N
SH
95 I bond /~ H trimethoxyphenyl
\ /
N= N
OH
96 1 bond \ H cyclohexyl
-~~'N
O
OH
97 1 bond \ H adamantyl
'N
O
OH
98 1 bond \N H 1,1-dimethylpropyl
~~ O
33

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
_ No. n D R2 A R1
OH
99 1 bond \N H trimethoxyphenyl
~~ O
N~
O
100 1 bond ~ H cyclohexyl
OH
N~
O
101 1 bond ~ H adamantyl
~OH
N~
O
102 1 bond ~ H 1,1-dimethylpropyl
OH
~N~O
103 1 bond ~ H trimethoxyphenyl
OH
OH
C
104 1 ,bond ~/ H cyclohexyl
NH
O
34

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
- No. n D R2 A Rl
OH
C
105 1 bond / H adamantyl
O
OH
C
106 1 bond ~/ H 1,1-dimethylpropyl
NH
O
OH
C
107 1 bond Y/ H trimethoxyphenyl
NH
0
O
108 1 bond ~NH H cyclohexyl
S ---
C
O
109 1 bond ~NH H adamantyl
S --
C

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
No. n D R2 A R1
O
110 1 bond ~NH H 1,1-dimethylpropyl
S-
C
O
111 1 bond ~NH H trimethoxyphenyl
S--
C
N~
~N
112 1 bond / H cyclohexyl
~- N H
F
N~
~N
113 1 bond ~ NH H adamantyl
F
N~
~N
114 1 bond / H l,l-dimethylpropyl
NH
F
N~
~N
115 1 bond / H trimethoxyphenyl
~- N H
F
36

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
No. n D R2 A Rl
N~
116 1 bond % H cyclohexyl
NH
HS
N~
117 1 bond % H adamantyl
NH
HS
N\N
118 1 bond ~ ~ H 1,1-dimethylprcb_yl
NH
HS
N~
119 1 bond % H trimethoxyphenyl
NH
HS
0
120 1 bond ~NH H cyclohexyl
HN-
C
0
121 1 - bond ~NH H adamantyl
HN
C
37

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
_ No, n D R2 A R1
O
122 1 bond ~NH H 1,1-dimethylpropyl
HN
\\0
O
123 1 bond ~NH H trimethoxyphenyl
HN-
C
O
124 1 bored ~-~-N~NH H cyclohexyl
O
\C
O
125 1
bond ~- N NH h adamantyl
O ~~
C
O
126' 1
bond ~ \ NH H l,l-dimethylpropyl
0
C
38

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
No. n D R2 A R1
0
127 1 bond
NH H trimethoxyphenyl
O
0
S
0
128 2 bond ~NH H cyclohexyl
C
O
129 1 bond ~NH H adamantyl
C
S
0
130 1 bond ~ NH H l,l-dimethylpropyl
\,
C
S
0
131 1 bond ~NH H trimethoxyphenyl
C
39

CA 02333960 2000-12-O1
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_ No. n D R2 A R1
O
OH
132 1 bond ~ H cyclohexyl
O
s
O
OH
133 1 bond H adamantyl
0
S
0
OH
134 1 bond H 1,1-dimethylpropyl
O
S
0
OH
135 1 bond H trimethoxyphenyl
O
Et
136 1 bond ~~ ~ H cyclohexyl
O - IV

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
No. n D R2 A Rl
N Et
137 1 bond ~~ ~ H adamantyl
0- N
Et
138 1 bond ~~ ~ H 1,1-dimethylpropyl
0- N
N Et
139 1 bond ~~ ~ H trimethoxyphenyl
O- N
/ N~
0
140 1 bond ~~ ~ H cyclohexyl
HN
~~S
/N~0
141 1 bond ~ H adamantyl
HN-
S
/ N~
0
142 1 bond ~ ~ H 1,1-dimethylpropyl
HN-
S
/ N~
O
143 1 bond ~ ~ H trimethoxyphenyl
HN
S
N Me
144 1 bond ~~ ,~ H cyclohexyl
S- N
41

CA 02333960 2000-12-O1
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No. n D R2 A R1
N Me
145 1 bond ~ H adamantyl
S- N
N Me
146 1 bond ~ H 1,1-dimethylpropyl
S- N
N Me
147 1 bond ~ H trimethoxyphenyl
S- N
~S
148 1 bond ~H H cyclohexyl
i
~S
149 1 bond ~H H adamantyl
~S
150 1 bond ~H H 1,1-dimethylpropyl
~S
151 1 bond ~ OH H trimethoxyphenyl
4?

CA 02333960 2000-12-O1
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Additional claimed or comparative carboxylic acids
and isosteres of N-heterocyclic compounds which also show
the remarkable neurotrophic and hair growth effects of
the present invention are shown below:
Y-~~n
R-a
~N~D
L
\ Rl
Cpd . n D Rz L R1
A 1 bond COOH 1,2-dioxoethyl 1,1-dimethylpropyl
B 2 bond COOH 1,2-dioxoethyl 1,1-dimethylpropyl
C 1 bond COOH SO= Benzyl
D 1 CHZ OH 1,2-dioxoethyl l,l-dimethylpropyl
E 1 bond tetrazole l,l-dimethylpropyl
I,2-dioxoethyl
F 1 bond -CN 1,2-dioxoethyl 1,1-dimethylpropyl
G 2 bond CONH2 1,2-dioxoethyl 1,1-dimethylpropyl
where Y Z are both carbon for
and compounds A-G,
H 1 bond COOH 1,2-dioxoethyl 1,1-dimethylpropyl
I 1 bond COOH 1,2-dioxoethyl i,l-dimethylpropyl
where Z S for compound H and
is
where Y S for compound I.
is
Pharmaceutical Compositions of the Present Invention
The present invention relates to a pharmaceutical
composition comprising:
(i) an effective amount of a urea or carbamate of
an N-heterocyclic carboxylic acid or carboxylic
acid isostere compound; and
(ii) a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceuti-
cal composition comprising:
43

CA 02333960 2000-12-O1
WO 99/62879 PCT/US98/25570
(i) an effective amount of a urea or carbamate of
an N-heterocyclic carboxylic acid or carboxylic
acid isostere compound for treating
neurodegenerative diseases, neurological
disorders, and nerve damage, or promoting nerve
growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceuti-
cal composition comprising:
(i) an effective amount of a urea or carbamate of
an N-heterocyclic carboxylic acid or carboxylic
acid isostere compound for treating alopecia or
promoting hair growth in an animal; and
(ii) a pharmaceutically acceptable carrier.
As neurotrophic agents, the compounds can be
administered with other neurotrophic agents such as
neurotrophic growth factor, brain derived growth factor,
filial derived growth factor, cilial neurotrophic factor,
insulin growth factor and active truncated derivatives
thereof, acidic fibroblast growth factor, basic
fibroblast growth factor, platelet-derived growth
factors, neurotropin-3 and neurotropin 4/5. The dosage
level of other neurotrophic drugs will depend upon the
factors previously stated and the neurotrophic
effectiveness of the drug combination.
Methods of the Present Invention
The ,present invention relates to the use of any of
the compounds described herein, in the preparation of a
medicament for the treatment of a disease such as
peripheral neuropathy caused by physical injury or
disease state, physical damage to the brain, physical
damage to the spinal cord, stroke associated with brain
damage, Alzheimer's Disease, Parkinson's Disease, and
amyctrophic lateral sclerosis. The present invention
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alsa relates to the use of carboxylic acid and carboxylic
acid isostere compounds for treating the above-mentioned
neuropathies, neurological disorders, and neurological
damage.
The present invention also relates to a method for
treating alopecia or promoting hair growth in an animal,
which comprises administering to said animal an effective
amount of a urea or carbamate of an N-heterocyclic
carboxylic acid or carboxylic acid isostere. The present
invention also relates to using the inventive compounds
and compositions in the preparation of a medicament for
the treatment of alopecia or promoting hair growth in an
animal.
The inventive method is particularly useful for
treating male pattern alopecia, alopecia senilis,
alopecia areata, alopecia resulting from skin lesions or
tumors, alopecia resulting from cancer therapy such as
chemotherapy and radiation, and alopecia resulting from
systematic disorders such as nutritional disorders and
internal secretion disorders.
It is understood, however, that a specific dose
level for any particular patient will depend upon a
variety of factors including the activity of the specific
compound employed, the age, body weight, general health,
sex, diet, time of administration, rate of excretion,
drug combination, and the severity of the particular
disease or disorder being treated and form of
administration.
MPTP Model of Parkinson's Disease in Mice
MPTP lesioning of dopaminergic neurons in mice was
used as an animal model of Parkinson's Disease. Four week
old male CD1 white mice were dosed i.p. with 30 mg/kg of
MPTP for 5 days. Inventive compounds (4 mg/kg), or
vehicle, were administered s.c. along with the MPTP for 5

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days, as well as for an additional 5 days following
cessation of MPTP treatment. At 18 days following MPTP
treatment, the animals were sacrificed and the striata
were dissected and homogenized. Immunostaining was
performed on saggital and coronal brain sections using
ant:-tyrosine hydoxylase Ig to quantitate survival and
recovery of dopaminergic neurons. In animals treated
with MPTP and vehicle, a substantial loss of functional
dopaminergic terminals was observed as compared to non-
lesioned animals. In another protocol, test compounds
were administered only subsequent to MPTP-induced
lesioning. Thus, after animals were treated with MPTP
for 5 days, an additional 3 days passed before beginning
oral drug treatment on day 8. Animals were treated with
inventive compounds (0.4 mg/kg), administered orally,
once a day for 5 days total. On day 18, the animals were
sacrificed and analyzed as described above. Table II
presents the percent recovery of dopaminergic neurons in
the first (concurrent dosing) paradigm in animals
receiving carboxylic acid or carboxylic acid isostere
compounds.
Table II, below, shows the remarkable
neuroregenerative effects of the inventive carboxylic
acid or carboxylic acid isostere related compounds
illustrating the neurotrophic capability of carboxylic
acid isosteres as a class showing that lesioned animals
receiving the carboxylic acid or carboxylic acid isostere
compounds provide a remarkable recovery of TH-stained
dopaminergic neurons.
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Table II - MPTp NeurodeQenerative Model
% Recovery
Compound A 26.7 %
Compound B ND
Compound C 24.4
Compound D 23.2 0
Compound E 19.6 a
Compound F 34.1 %
Compound G 46.5 %
Compound H 14.0 0
Compound I ND
Percent striatal innervation density was quantitated
in brain sections with an anti-tyrosine hydroxylase
immunoglobulin, which is indicative of functional
dopaminergic neurons. The striatal innervation density
of 23% for animals pretreated with only a vehicle and
administered a vehicle orally during treatment, is
indicative of normal non-lesioned striatal tissue.
Stri.atal innervation density is reduced to 5% for animals
pretreated with MPTP and administered a vehicle orally
during treatment, and is indicative of MPTP-induced
lesioning. Surprisingly, striatal innervation density is
increased 8%-13% for animals pretreated with MPTP and
administered 0.4 mg/kg orally during treatment,
indicating substantial neuronal regeneration after
induction of MPTP-derived lesions.
In Vivo Hair Generation Test With C57 Black 6 Mice
C57 black 6 mice are used to demonstrate the hair
revitalizing properties of the ureas and carbamates of N-
heterocyclic carboxylic acids or carboxylic acid
isosteres. Referring now to FIGS. 1 and 2 of the
drawings, C57 black 6 mice, approximately 7 weeks old,
had an area of about 2 inches by 2 inches on their
47

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hindquarters shaved to remove all existing hair. Care
was taken not to nick or cause abrasion to the
underlaying dermal layers. The animals were in anagen
growth phase, as indicated by the pinkish color of the
skin. Referring now to FIG. 2, four animals per group
were treated by topical administration with 20o propylene
glycol vehicle (FIG. 2), or related compounds dissolved
in the vehicle. The animals were treated with vehicle or
N-heterocyclic carboxylic acids or isosteres every 48
hours (3 applications total over the course of 5 days)
and the hair growth was allowed to proceed for 6 weeks.
Hair growth was quantitated by the percent of shaved area
covered by new hair growth during this time period.
FIG. 2 shows that animals treated with vehicle
exhibited only a small amount of hair growth in patches
or tufts, with less than 3% of the shaved area covered
with new growth.
In contrast, FIG. 3 shows that animals treated for 2
weeks with the N-heterocyclic carboxylic acid compounds
i.e. compound A, compound B, and compound G exhibited
dramatic hair growth, covering greater than 25% of the
shaved area in all animals for two of the compounds.
FIG. 3 shows the relative hair growth on shaven C57
black 6 mice 7.4 days after being treated with N-
heterocyclic carboxylic acids or carboxylic acid
isost:eres. The mice had a 2 x 2 inch region on their
backside shaved to remove all hair. Care was taken not
to nick or cause abrasion to the underlying dermal
layers. Compounds at a concentration of 1 umole per
milliliter were carefully applied to the shaved area of
the mice (5 mice per group) three times per week. Hair
growth was evaluated 14 days after initiation of drug
treatment. The relative scale for assessing hair growth
is as follows:
0 = no growth;
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1 = beginning
of
growth
in
small
tufts;
2 = hair growthcovering over <250 of shaved area;
3 = hair growthcovering over >250 of shaved area, but
less than 500 of shaved area;
4 - hair growthcovering over >500 of shaved area, but
less than 750 of shaved area;
5 = complete hair growth of shaved area.
The following examples are illustrative of preferred
embodiments of_ the invention and are not to be construed
as limiting the invention thereto. All polymer molecular
weights are mean average molecular weights. All
percentages are based on the percent by weight of the
final delivery system or formulation prepared unless
otherwise indicated and all totals equal 1000 by weight.
EXAMPJ~ES
The inventive compounds may be prepared by a variety
of synthetic sequences that utilize established chemical
transformations. An exemplary general pathway to
synthesize the present compounds is described in Scheme
I.
SCHEME I
'N"COOMe
N COOMe Cyclohexyl
H isocyanate ~ LiOH /MeOH
HN' \ 0
CHZC12, Et3N
~COOH
HN " 0
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_ EXAMPLE I ( Co~zpound 1 )
Synthesis of (2S)-1-fN-cyclohexylcarbamoyl)
pyrrolidine-2-carboxylic acid
a. Methyl (2S)-1-(N-cyclohexylcarbamoyl)pyrrolidine-2-
carboxylate.
A mixture of cyclohexyl isocyanate (3.88 g; 31
mmol), L-proline ester hydrochloride (5.0 g; 30.19 mmol),
and triethylamine (9 mL) in methylene chloride (150 ml)
was stirred overnight at room temperature. The reaction
mixture was washed with 2 x 100 ml of 1 N HCL and 1 x 100
ml of water. The organic phase was dried, concentrated
and purified on a silica gel column (50 o EtOAc/hexane)
to yield the urea as a thick oil, 1H NMR (CDC13, 400 MHz):
d 1.09-1.15 (m, 3H); 1.33 (m, 2H); 1.68 (m, 3H); 1.93-
2.05 (m, 6H); 3.33 (m, 1H); 3.43 (m, 1H); 3.46 (m, 1H);
3.73 (s, 3H); 4.39 (m, 1H); 4.41 (m, 1H).
b. (2S)-1-(N-cyclohexylcarbamoyl)pyrrolidine-2-
carbo:~ylic acid.
Methyl (2S)-1-(N-cyclohexylcarbamoyl)pyrrolidine-2-
carboxylate (3.50 g) was dissolved in methanol (60 ml),
cooled to 0°C, and treated with 2N LiOH (20 ml). After
stirring overnight, the mixture was partitioned between
ether and water. The ether layer was discarded and the
aqueous layer was made acidic (pH 1) with 1N HC1 and
extracted with methylene chloride. Drying and removal of
the solvent provided 2.20 g of the product as a white
solid, 1H NMR (CDC13, 400 MHz): d 1.14-1.18 (m, 3H); 1.36-
1.38 (m, 2H); 1.71-1.75 (m, 3H); 1.95-2.04 (m, 5H); 2.62
(m, 1H); 3.16 (m, 1H); 3.30-3.33 (m, 1H); 3.67 (m, 1H);
4.38 (br, 1H); 4.46 (m, 1H).

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_ Example 2
A lotion comprising the following composition may be
prepared.
( o)
95o Ethanol 80.0
a urea or carbamate derivative of N- 10.0
hete rocyclic carboxylic acid or carboxylic
acid isostere
a-Tocopherol acetate 0.01
Ethylene oxide (40 mole) adducts of hardened 0.5
castor oil
purified water 9.0
perfume and dye q,s,
Into 95o ethanol are added a urea or carbamate
derivative of N-heterocyclic carboxylic acid or
carboxylic acid isostere, a-tocopherol acetate, ethylene
oxide (40 mole) adducts of hardened castor oil, perfume
and a dye. The resulting mixture is stirred and
dissolved, and purified water is added to the mixture to
obtain a transparent liquid lotion.
5 ml of the lotion may be applied once or twice per
day to a site having marked baldness or alopecia.
Example 3
,?~ lotion comprising the following composition shown
may be prepared.
95o Ethanol 80.0
a urea or carbamate derivative of N- 0.005
heterocyclic carboxylic acid or carboxylic
acid isostere
Hinokitol 0.01
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Ethylene oxide (40 mole) adducts of 0.5
hardened castor oil
Purified water 19.0
Perfume and dye a. s
.
Into 95o ethanol are added a urea or carbamate
derivative of N-heterocyclic carboxylic acid or
carboxylic acid isostere, hinokitol, ethylene oxide (40
mole) adducts of hardened castor oil, perfume, and a dye.
The resulting mixture is stirred, and purified water is
added to the mixture to obtain a transparent liquid
lotion.
The lotion may be applied by spraying once to 4
times per day to a site having marked baldness or
alope~cia .
Example 4
An emulsion may be prepared from A phase and B phase
having the following compositions.
(A phase) (o)
Whale wax 0.5
Cetanol 2.0
Petrolatum 5.0
Squalane 10.0
Polyoxyethylene (10 mole) monostearate 2.0
Sorbitan monooleate 1.0
a urea or carbamate derivative of N- 0.01
hete~rocyclic carboxylic acid or carboxylic
acid isostere
(B phase)
( o)
Glycerine 10.0
Purified water 69.0
Perfume, dye, and preservative q.s.
The A phase and the B phase are respectively heated
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_ and melted and maintained at 80°C. Both phases are then
mixed and cooled under stirring to normal temperature to
obtain an emulsion.
The emulsion may be applied by spraying once to four
times per day to a site having marked baldness or
alopecia.
Examtale 5
A cream may be prepared from A phase and B phase
having the following compositions.
(A Phase) (o)
Fluid paraffin 5.0
Cetostearyl alcohol 5.5
Petrolatum 5.5
Glycerine monostearate 33.0
1S Polyoxyethylene (20 mole) 2-octyldodecyl 3.0
ether
Propylparaben 0.3
(B Phase) (%)
a urea or carbamate derivative of N- 0.8
heterocyclic carboxylic acid or
carboxylic acid isostere
Glycerine 7.0
Dipropylene glycol 2C.0
Polyethylene glycol 4000 5.0
Sodium Hexametaphosphate 0.005
Purified water 44.895
The A phase is heated and melted, and maintained at
70°C. The B phase is added into the A phase and the
mixture is stirred to obtain an emulsion. The emulsion
is then cooled to obtain a cream.
The cream may be applied once to 4 times per day to
a site having marked baldness or alopecia.
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Examm~.le 6
A liquid comprising the following composition may be
prepared.
(o)
Polyoxyethylene butyl ether 20.0
Ethanol 50.0
a urea or carbamate derivative of N- 0.001
heterocyclic carboxylic acid or carboxylic
acid isostere
Propylene glycol 5.0
Polyoxyethylene hardened castor oil 0.4
derivative (ethylene oxide 80 mole
adducts )
Peri:ume q. s
.
Purified water q.s.
Into ethanol are added polyoxypropylene butyl ether,
propylene glycol, polyoxyethylene hardened castor oil, a
urea or carbamate derivative of N-heterocyclic carboxylic
acid or carboxylic acid isostere, and perfume. The
resulting mixture is stirred, and purified water is added
to the mixture to obtain a liquid.
The liquid may be applied once to 4 times per day to
a site having marked baldness or alopecia.
Example 7
A shampoo comprising the following composition may be
prepared.
( o)
Sodium laurylsulfate 5.0
Triethanolamine laurylsulfate 5.0
Betaine lauryldimethylaminoacetate 6.0
Ethylene glycol distearate 2.0
Pol ethylene 1 col 5.0
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a urea or carbamate derivative of N- 5.0
heterocyclic carboxylic acid or carboxylic
acid isostere
Ethanol 2.0
Perfume 0.3
Purified water 69.7
Into 69.7 of purified water are added 5.0 g of sodium
laurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0
g of betaine lauryldimethyl-aminoacetate. Then a mixture
obtained by adding 5.0 g of a urea or carbamate.derivative
of N-heterocyclic carboxylic acid or carboxylic acid
isostere, 5.0 g of polyethylene glycol, and 2.0 g of
ethylene glycol distearate to 2.0 g of ethanol, followed by
stirring, and 0.3 g of perfume are successively added.
The resulting mixture is heated and subsequently cooled to
obtain a shampoo.
The shampoo may be used on the scalp once or twice per
day.
Example 8
A patient is suffering from alopecia senilis. A urea
or carbamate derivative of N-heterocyclic carboxylic acid
or carboxylic: acid isostere, or a pharmaceutical
composition comprising the same, may be administered to the
patient. Increased hair growth is expected to occur
following treatment.
Example 9
A patient is suffering from male pattern alopecia. A
urea or carbamate derivative o.f N-heterocyclic carboxylic
acid or carboxylic acid isostere, or a pharmaceutical
composition comprising the same may be administered to the
patient. Increased hair growth is expected to occur
following treatment.

CA 02333960 2000-12-O1
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- Example 10
A patient is suffering from alopecia areata. A urea
or carbamate derivative of N-heterocyclic carboxylic acid
or carboxylic acid isostere, or a pharmaceutical
composition comprising the same, may be administered to the
patient. Increased hair growth is expected to occur
following treatment.
Example 11
A patient is suffering from hair loss caused by skin
lesions. A urea or carbamate derivative of N-heterocyclic
carboxylic acid or carboxylic acid isostere, or a
pharmaceutical composition comprising the same, may be
administered to the patient. Increased hair growth is
expected to occur following treatment.
Examgle 12
A patient is suffering from hair loss caused by
tumors. A urea or carbamate derivative of N-heterocyclic
carboxylic acid or carboxylic acid isostere, or a
pharmaceutical composition comprising the same, may be
administered to the patient. Increased hair growth is
expected to occur following treatment.
Example 13
A patient. is suffering from hair loss caused by a
systematic disorder, such as a nutritional disorder or an
internal secretion disorder. A urea or carbamate
derivative of N-heterocyclic carboxylic acid or carboxylic
acid isostere, or a pharmaceutical composition comprising
the same; may be administered to the patient. Increased
hair growth is expected to occur following treatment.
ExamQle 14
A patient. is suffering from hair loss caused by
chemotherapy. A urea or carbamate deriva~ive of N-
heterocyclic carboxylic acid or carboxylic acid isostere,
or a pharmaceutical composition comprising the same, may be
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administered to the patient. Increased hair growth is
expected to occur following treatment.
Example 15
A patient is suffering from hair loss caused by
radiation. A urea or carbamate derivative of N-
heterocyclic carboxylic acid or carboxylic acid isostere,
or a pharmaceutical composition comprising the same may, be
administered to the patient. Increased hair growth is
expected to occur following treatment.
Example 16
A patient is suffering from a neurodegenerative
disease. A carboxylic acid or carboxylic acid isostere of
an N-heterocyclic ring or a pharmaceutical composition
comprising the same is administered. :Lt would be expected
that the patient would improve their condition or recover.
Example 17
A patient is suffering from a neurological disorder.
A carboxylic acid or carboxylic acid isostere of an N-
heterocyclic ring or pharmaceutical compositions comprising
same is administered. It would be expected that the
pati<~nt would improve their condition or recover.
Example 18
A patient is suffering from stroke. A carboxylic acid
or carboxylic acid isostere of an N-heterocyclic ring or
pharmaceutical compositions comprising same is
administered. It would be expected that the patient would
improve their condition or recover.
Example 19
A patient is suffering from Parkinson's Disease. A
carboxylic acid or carboxylic acid isostere of an N-
heter_ocyclic ring or pharmaceutical compositions comprising
same is administered. It would be expected that the
patient would improve their condition or recover.
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_ Example 20
A patient is suffering from Alzheimer's Disease. A
carboxylic acid or carboxylic acid isostere of an N-
heterocyclic ring or pharmaceutical compositions comprising
same is administered. It would be expected that the
patient would improve their condition or recover.
Example 21
A patient is suffering from a peripheral neuropathy.
A carboxylic acid or carboxylic acid isostere of an N-
heterocyclic ring or pharmaceutical compositions comprising
same is administered. It would be expected that the
patient would improve their condition or recover.
Example 22
A patient is suffering from amyotrophic lateral
sclerosis. A carboxylic acid or carboxylic acid isostere
of an N-heterocyclic ring or pharmaceutical compositions
comprising same is administered. It would be expected that
the patient would improve their condition or recover.
Example 23
A patient is suffering from a spinal injury. A
carboxylic acid or carboxylic acid isostere of an N-
heterocyclic ring or pharmaceutical compositions comprising
same is administered. It would be expected that the
patient would improve their condition or recover.
Example 24
A patient is at risk of suffering from a
neurodegenerative disease or neurological disorder. A
carboxylic acid or carboxylic acid isostere of an N-
heterocyclic ring or a pharmaceutical composition
comprising the same is prophelactically administered. It
would be expected that the patient would be prevented from
some or all of the effects of the disease or disorder, or
would significally improve their condition or recover over
patients who were not pre-treated.
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_ The invention being thus described, it will be obvious
that the same may be varied in many ways. Such variations
are not to be regarded as a departure from the spirit and
scope of the invention and all such modification are
intended to be included within the scope of the following
claims.
59

Representative Drawing